The overall goals of this project are to conduct comprehensive clinical studies to test our central hypothesis that hyperthermia (HT) as an adjuvant to radiation (RT) and chemotherapy (CTx) will improve complete response rates, local control and overall survival in patients with tumors of of extremities, breast and pelvis. In the last grant period we successfully conducted and completed seven clinical trials. The results of these studies provide compelling rationale for the design of this new project. This project encompasses four specific aims. 1) Test the feasibility and accuracy of non-invasive thermometry in patients with extremity soft tissue sarcomas, melanomas, breast tumors, and pelvic malignancies. 2) Conduct an international multiinstitutional phase III trial testing the use of HT with RT and CTx in potentially curable patients with locally advanced cervix cancer (LACC). 3) Examine use of HT to augment tumor drug delivery with temperature non-sensitive and temperature-sensitive liposomes in breast carcinoma. 4) Examine the interrelationships between hyperthermia, tumor physiology, and gene expression. We continue to battle some of the most aggressive, locally advanced tumors seen in modern oncology practice. These include inflammatory and LABC, large high-grade sarcomas, in-transit melanoma, and LACC. Adding HT to the best conventional therapies and using novel HT-guided drug delivery systems for these cancers may well prove to increase local control and survival. The accompanying ancillary studies will help us to understand and optimize HT interactions and may also clarify the interrelationship of genomics and tumor physiology. Should these clinical efforts be successful, the parallel development of 3-dimensional (3-D) non-invasive thermometry techniques for monitoring and controlling HT will ultimately make the delivery of a well-defined HT dose feasible and practical for the broader oncologic community